Abstract Pancreatic adenocarcinoma (PDAC) is a lethal disease, the fourth-leading cause of cancer-related death in the United States. Metastasis is responsible for 90% of the cancer-related deaths. Expression of MUC16 (50-60%) is highly associated with metastatic pancreatic cancer. We recently discovered that cancer associated isoforms of CA125/MUC16 have biological activity: cancer associated forms of the MUC16 glycoprotein contain multivalent ligands with high avidity for epidermal growth factor receptor (EGFR1, 2 and 3) and integrin (?4/?1) complexes, which results in constitutive activation of signaling cascades that include Akt and FAK and concomitant increases in the oncogenic potential of pancreatic cancer cells. Interestingly, these activities were enhanced by aberrant (truncated) O-glycosylation of MUC16. This finding together with our recent documentation of the widespread expression of MUC16 in metastatic pancreatic cancer, suggest that in addition to serving as a biomarker for adenocarcinoma, MUC16 can function as an oncogenic cytokine or growth factor. Further, whole genome analyses of clinical samples of PDAC have revealed that MUC16 is among the most highly mutated genes in pancreatic cancer. Hence, in addition to serving as a biomarker for adenocarcinomas, we hypothesize that tumor associated and mutated forms of circulating CA125/MUC16 have biological roles as a growth factor or cytokines that may contribute to paracrine oncogenic signaling interactions in the distant organ sites that may contribute to tumor progression and secondary effects of tumor growth. Our long term goal is to determine the molecular and biological mechanisms by which MUC16 mediates tumor aggressiveness, progression, early metastasis and systemic effects of cancer progression. To achieve this, we propose to investigate the hypothesis that site specific mutation contributes to activation of biologically active isoforms and/or proteolytic cleavage of MUC16, and evaluate the biological activity in cell based models of pancreatic cancer (Aim 1). We will investigate contribution of mutated MUC16 to tumor progression in an in vivo orthotopic pancreas tumor model system (Aim 2). We will determine the sites of mutation on MUC16, and investigate its biological functions in clinical specimens of pancreatic cancer (Aim 3). These studies will lead to a new understanding of the function and effects of secreted tumor products that are biomarkers on tumor growth, metastasis to distant organ sites, configuration of the tumor microenvironment and other aspects of tumor progression.